Heart failure is characterized both by an activation of the
endothelin system and an increased
vasoconstrictor contractile response to the
peptide. Given its pharmacological profile, it is likely that
endothelin (ET-1) plays a deleterious role in the development of
heart failure, and that blockers of the
endothelin system are beneficial in this disease. Indeed, in rats with
heart failure, ET(A) and dual ET(A)-ET(B) receptor antagonists reduce arterial pressure as well as left ventricular end diastolic pressure. The same antagonists also prevent the degradation of left ventricular function, as evidenced by the increased left ventricular fractional shortening and wall thickening. ET(A) and ET(A)-ET(B) antagonists also reduce LV dilatation and LV
fibrosis, but do not affect LV
hypertrophy. Moreover, comparison between selective ET(A) and combined ET(A)-ET(B) antagonists reveal no differences in terms of their effects on blood pressure, LV hemodynamics or remodeling. However, only combined ET(A)-ET(B) antagonists significantly decreased heart rate. ET(B) antagonists alone do not affect blood pressure or LV hemodynamics, but reduce LV
fibrosis. With regard to survival, we have shown that long term treatment with the dual ET(A)-ET(B) antagonist
bosentan increased survival to the same extent as an
angiotensin converting enzyme inhibitor. However, the effect of selective ET(A) antagonists on survival is more controversial, since we found that the non-
peptide ET(A) antagonists
LU 135252 did not affect survival of rats with
myocardial infarction, while others have shown that the
peptide ET(A) antagonist
BQ-123 increased survival in the same model. These conflicting data regarding the efficacy of selective ET(A) vs dual ET(A)-ET(B) blockade points out the need for controlled long term studies comparing the effects of theses two pharmacological approaches on survival.